The surprise thumbs-down recently by the FDA for Celgene Corp.'s ozanimod to treat relapsing multiple sclerosis (MS) echoed the disappointment last year with mongersen (GED-0301) for Crohn's disease (CD), but apparently didn't affect late-stage work with the former compound in ulcerative colitis (UC) and CD.

U.S. regulators smacked Summit, N.J.-based Celgene with a refusal to file letter on the NDA for ozanimod, an oral selective sphingosine 1-phosphate (S1P) 1 and 5 receptor modulator that the firm brought aboard as part of the $7.2 billion acquisition of Receptos Inc., of San Diego. The candidate bore a five-year consensus sales forecast of $1.63 billion, according to Cortellis Competitive Intelligence. (See BioWorld Today, March 1, 2018.)

With mongersen, an oral SMAD7 antisense oligonucleotide, the situation was different but also less than pleasing. In October 2017, Celgene halted the phase III trial called Revolve in CD as well as an extension study after hearing results from the data monitoring committee's interim futility analysis. The company also decided against starting the phase III CD trial called Define and said it would review the full phase II mongersen dataset in UC to determine the next steps in that indication. (See BioWorld Today, Oct. 23, 2017.)

The scenario was serious enough that RBC Capital Markets analyst Brian Abrahams suggested that Celgene, especially given the mid-2020's patent cliff faced by Revlimid (lenalidomide), might consider going private by way of a leveraged buyout. In a report Wednesday, he called the move a "theoretical win-win for all parties," allowing the company to "better capture the medium-term value from future Revlimid cash flows pre-cliff, not being appreciated by the public markets, and avoid valuation volatility as [the company works through] additional Revlimid litigation/settlements and pipeline developments (e.g., ozanimod re-filing)." The move would marginally reduce general and administrative costs, he said.

As pundits mull the fortunes of Celgene, an even wider question involves the future of therapies for CD and UC, indications subsumed under the umbrella of inflammatory bowel disease (IBD) – "one of the most underserved inflammatory disease markets by biologic therapeutics," Leerink analyst Geoffrey Porges wrote in a research report last November.

That's changing. Although anti-TNF drugs such as Humira (adalimumab, Abbvie Inc.) and Remicade (infliximab, Janssen Biotech Inc.) have held most of the $9 billion IBD market for about two decades, oral immune-modifying drugs are coming down the pike in the S1P and JAK inhibitor classes, not to mention added injectable therapies that could help mild to moderate patients as well as the more severe, treatment-refractory cases.

It's about time, considering that other inflammatory disorders such as rheumatoid arthritis (RA) and psoriasis can boast a half dozen drug classes targeting them, and that IBD with anti-TNFs only is often not well handled and patients tend to cycle through. The anti-integrin Entyvio (vedolizumab, Takeda Pharmaceuticals U.S.A. Inc.) won FDA clearance in 2014 and Stelara (ustekinumab, Janssen Biotech Inc.) in 2016. Steps in the right direction, but there's still a need for more.

Bittoo Kanwar, senior medical director and gastroenterologist with Protagonist Therapeutics Inc., said the field is "shifting away from biologic therapies, and there's a new era, so to speak, of oral compounds," including those in development by his Newark, Calif.-based firm: PTG-100, in a phase II trial for UC, and PTG-200, due to enter phase II investigation in the hands of partner Janssen Biotech Inc., of Horsham, Pa. (See BioWorld Today, May 31, 2017.)

"We're testing the hypothesis of gut restriction, which is pretty new to the field," he said. PTG-100's target, the alpha-4-beta-7 integrin, is the same as that of Entyvio. PTG-200 takes aim at the IL-23 receptor, the same as Stelara. IL-23 is "very involved in Crohn's, especially," he said, and the likes of North Chicago-based Abbvie Inc. as well as Eli Lilly and Co., of Indianapolis, have done work with antibodies that target P19, a subunit of IL-23, which resulted in "amazing efficacy," he said. "We think being specific to IL-23 over IL-12 will have immense safety and efficacy benefits."

The need for new IBD drugs gained urgency this month with disclosure of findings at the American College of Cardiology's annual scientific session. An analysis of medical record data from more than 17.5 million patients found that people with IBD are at elevated risk for a heart attack, regardless of whether they have traditional risk factors for heart disease such as high cholesterol, high blood pressure and smoking. People between the ages of 18 and 24 are in particular danger, with about nine times the risk of a heart attack compared to their peers in the same age group who don't have IBD, and that risk declined with age.

"The theory as to why [the higher risk turns up in younger patients] is unclear, but in general whenever somebody has a pro-inflammatory state, their risk of things such as thrombosis, cardiac events, lipid abnormalities are increased at baseline," Kanwar said.

In the study, researchers identified adult patients ages 18 to 65 diagnosed with IBD between 2014 and 2017. Of the patients in the database, 211,870 (1.2 percent) had the condition, in line with previously gathered statistics. Those with the condition were found more likely to be smokers and to have diabetes, high blood pressure and high cholesterol than those without. Heart attacks occurred about twice as often in people with IBD. Numbers were adjusted for heart disease risk factors and other demographics, and findings disclosed that IBD patients had a 23 percent higher risk of heart attack. Under age 40, the risk was greater for women than men, but after age 40 it leveled out.

Scenario similar to HCV, back when

Before the advent of anti-TNF therapies, "we used to throw corticosteroids at patients," Kanwar said. "When the TNFs came on the market, there was a transformative shift in the way we manage our patients." What's been learned since, "primarily via the infliximab history," is that treated patients "feel better within a day. It is remarkable to see in the clinic. With Humira, it's a slightly delayed reaction but there's still that response."

The problem is that it doesn't last. "For the first six to 12 weeks, even maybe through week 14, these patients are doing really well, they're feeling great, but they lose response over time," he said. Entyvio is the same way. A key to efficacy is determining "what the peripheral levels of antibody are at trough, meaning right before your next dose – every two months in the case of Entyvio and Remicade, during the maintenance phase – what are the levels? If those trough levels are too low, we know that is associated with the loss of response. What clinicians are now doing is therapeutic drug monitoring of at-trough [levels], and if the patient is too low they have the option to maybe double the dose the next time or decrease the interval by which we dose. That has resulted in much better clinical outcomes. My god, it took us five to 10 years to figure that out," he said, but such is "the complexity associated with monoclonal antibodies."

In the oral JAK1 space for IBD, Foster City, Calif.-based Gilead Sciences Inc. has phase III filgotinib and Abbvie is working with upadacitinib, also late stage. The idea is that "if you can target JAK1, you get away from some of the side effects associated with JAK inhibition," Kanwar said. "If you target JAK1 over JAK2, you don't get the hematologic abnormalities and if you stay away from JAK3, you may have protection [against] lipid abnormalities."

Pfizer Inc., of New York, has tofacitinib, recently the subject of an FDA advisory panel meeting. The compound "was received relatively well. Their data are quite good in terms of efficacy in UC. For whatever reason, it failed in CD. We're kind of unclear why." Approved as Xeljanz for RA, the drug carries a black box warning for infection and risk of malignancy. "That is something that the field and gastroenterologists will keep a close eye on," he said.

S1P therapies, for their part, prevent lymphocyte egress from lymph nodes. It's sort of similar to targeting alpha-4-beta-7, which prevents lymphocytes from entering the gut," Kanwar said. Another player in that space is San Diego-based Arena Pharmaceuticals Inc.'s etrasimod (APD-334). "They believe it has more selectivity, maybe [will be] the next generation beyond ozanimod, with potentially a better safety profile, but the data have to pan out." Phase II results in UC are expected this month.

Another firm with a still different oral IBD approach is Ann Arbor, Mich.-based Lycera Corp., which is conducting a phase II experiment to test LYC-30937-EC, an ATPase modulator, in UC. The study is expected to enroll up to 120 patients and is designed to assess the efficacy and safety of the compound, given orally once daily. Patients will be randomized on a 1-to-1 basis to receive either treatment with LYC-30937-EC or placebo. Subjects will be treated for eight weeks, with an additional two-week safety follow-up. The primary efficacy endpoint will be the proportion of subjects who achieve clinical remission at week eight using a modified Mayo score, while safety will be measured over 10 weeks. Lycera expects to complete the study this year.

Which oral IBD candidates will be most successful is hard to guess, but "there's always going to be a safety concern with TNFs, JAKs, anything that's systemic," Kanwar said. What's more, "patients hate going to infusion centers, and they'd rather not give themselves an injection," so convenience is an element. But what patients want most, of course, is efficacy. "It's an exciting time in the field," he said. "I was at Gilead before I was here and IBD right now feels like what hepatitis C felt like three or four years ago."

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